18F-labeled pyrazolo[1,5-a]pyrimidine derivatives: Synthesis from 2,4-dinitrobenzamide and tosylate precursors and comparative biological evaluation for tumor imaging with positron emission tomography

Abstract

We previously reported 18F-labeled pyrazolo[1,5-a]pyrimidine derivatives: 7-(2-[ 18F]fluoroethylamino)-5-methylpyrazolo[1,5-a] pyrimidine-3-carbonitrile ([ 18F]1) and N-(2-(3-cyano-5- methylpyrazolo[1,5-a]pyrimidin-7-ylamino)ethyl)-2-[ 18F]fluoro-4- nitrobenzamide ([ 18F]2). Preliminary biodistribution experiments of both compounds showed s slow clearance rate from excretory tissues which warranted further investigation for tumor imaging with PET. Here we modified [ 18F]1 and [ 18F]2 by introducing polar groups such as ester, hydroxyl and carboxyl and developed three additional 18F-18 labeled pyrazolo[1,5-a] pyrimidine derivatives: (3-Cyano-7-(2-[ 18F]fluoroethylamino)pyrazolo[1,5-a]-pyrimidin-5- yl)methyl acetate ([ 18F]3), 7-(2-[ 18F]fluoroethylamino)-5-(hydroxymethyl) pyrazolo[1,5-a]- pyrimidine-3-carbonitrile ([ 18F]4) and (S)-6-(3-cyano-5-methylpyrazolo[1,5-a]pyrimidin-7- ylamino)-2-(2-[ 18F]fluoro-4-nitrobenzamido)hexanoic acid ([ 18F]5). The radiolabeled probes were synthesized by nucleophilic substitution of the corresponding tosylate and nitro precursors with 18F-fluoride. In Vitro studies showed higher uptake of [ 18F]3 and [ 18F]4 than that of [ 18F]5 by S180 tumor cells. In Vivo biodistribution studies in mice bearing S180 tumors showed that the uptake of both [ 18F]3 and [ 18F]4 in tumors displayed an increasing trend while the uptake of [ 18F]5 in tumor decreased through the course of the 120 min study. This significant difference in tumor uptake was also found between [ 18F]1 and [ 18F]2. Thus, we compared the biological behavior of the five tracers and reported the tumor uptake kinetic differences between 2-[ 18F]fluoroethylamino- and 2-[ 18F]fluoro-4-nitro- benzamidopyrazolo[1,5-a] pyrimidine derivatives. © 2012 by the authors.